1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, commonly known as Apixaban (BMS-562247-01) is an anticoagulant for the prevention of venous thromboembolism and venous thromboembolic events. Apixaban is marketed under the trade name “Eliquis” and is being developed in a joint venture by Pfizer and Bristol-Myers squibb.
Lactam containing compounds, their derivatives and process for their preparation was first disclosed in U.S. Pat. No. 6,967,208B2. The disclosed process involves the usage of 1-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one (2) (herein after referred as “morpholine substituted lactam compound”) an intermediate for the preparation of Apixaban. The preparation of said morpholine substituted lactam compound is represented below:

The above said process involves the preparation of compound (2) by condensing the compound (1) with morpholine which involves the use of an excess amount of morpholine. When the above said reaction was repeated in the laboratory, it was found that an excess amount of morpholine is consumed, and apart from this the yields and purity of compound (2) were found to be very low. This can be attributed to the use of excess morpholine which leads to the formation of di-morpholine substituted compound as a by-product. Moreover, the conversion of di-morpholine substituted compound into mono-morpholine substituted compound (2) is a tedious task thereby increasing the cost of the production. Hence the said process is not suitable for the commercial level process.
In order to overcome this, a process involving a novel intermediate (which contains only one chlorine atom) was developed which during condensation avoids the consumption of excess morpholine to provide compound (2).
Crystalline solvates DMF-5 and FA-2 of Apixaban are disclosed in US2007203178A1; the crystalline forms N-1 and H2-2 of Apixaban are disclosed in U.S. Pat. No. 7,396,932B2; and the crystalline forms-I and II of Apixaban are disclosed in IPCOM000216217D.
The crystalline or polymorphic form may give rise to thermal behavior different from that of the amorphous material or another crystalline or polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and may be used to distinguish some crystalline or polymorphic forms from others. A particular crystalline or polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by X-ray powder diffraction (XRPD), solid state nuclear magnetic resonance (NMR) spectrometry, Raman spectroscopy and infrared (IR) spectrometry.
In deciding which polymorph or crystalline form is preferable, the numerous properties of the polymorphs or crystalline forms must be compared and the preferred polymorph or crystalline form chosen based on the many physical property variables. It is entirely possible that one polymorph or crystalline form can be preferable in some circumstances in which certain aspects, such as ease of preparation, stability, etc., are deemed to be critical. In other situations, a different crystalline form or polymorph may be preferred for greater solubility and/or superior pharmacokinetics.
The discovery of new crystalline or polymorphic forms of active pharmaceutical ingredient always provides a new opportunity to improve the performance characteristics of a desired pharmaceutical product.
The present inventors have developed novel crystalline forms which have greater free flow characteristics, consistently reproducible and suitable for the pharmaceutical formulations.